Previous studies showed repurposed drugs Clofazimine and Benidipine had antichagasic activity in acute and chronic Trypanosoma cruzi (T. cruzi) infection models as monotherapies. This study evaluated combinations of these drugs with low-dose Benznidazole (BZ, first-choice treatment in Argentina) against intracellular T. cruzi amastigotes in vitro and in a chronic murine model. In vitro, both BZ+Clofazimine and BZ+Benidipine combinations exhibited additive/synergistic effects (synergy scores >0) across four reference models (Bliss, Loewe, HSA, ZIP) with no cytotoxicity to Vero cells. In vivo, all treatments reduced blood parasite burden (quantified by qPCR) vs. untreated controls, with Clofazimine+BZ 30 showing greater reduction than BZ 30 monotherapy. While tissue (skeletal/cardiac muscle) parasite burden differences were not statistically significant, trends toward reduction were observed. Combined therapies reduced inflammation (e.g., fewer adipocytes in skeletal muscle) compared to BZ alone, and low-dose BZ combinations avoided the body weight loss seen with high-dose BZ (75 mg/kg) monotherapy. These findings support that repurposed drugs combined with low-dose BZ could be alternatives for chronic Chagas disease, with synergistic in vitro interactions indicating adjusted dosing regimes can improve in vivo therapeutic efficacy.